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Safety Evaluation of Recombinant Staphylokinase in Rhesus Monkeys
Qiujun Lu
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China, luqj{at}nic.bmi.ac.cn
Yuanmin Li
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China
Liqing Wen
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China
Shaoming Guo
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China
Yuanyuan Chen
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China
Weijing Liu
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China
Yue Gao
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China
Lingmao Ding
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China
Recombinant staphylokinase (rSTAR) is a profibrinolytic agent of bacterial origin. The objective of this study was to assess the toxicity of rSTAR administered with bolus intravenous infusion in rhesus monkeys (2/sex/group) at the dosages of 0, 4, 14, and 49 mg/kg/day for 2 weeks. The clinical signs were thickening of the skin in all animals and mild hematoma formation in three dosage groups at the injection sites. There were no effects on body weight, absolute or relative organ weights, ophthalmology, or electrocardiogram. Urinalysis indicated that 2 monkeys in 14 or 49 mg/kg/day group developed proteinuria and mild hematuria. Increases in serum BUN levels (14 and 49 mg/kg/day), ALT activity, and bilirubin levels (49 mg/kg/day), and decreases in red blood cell counts, hemoglobin concentrations and Hct values (49 mg/kg/day) were observed at week 2. Significant prolongation of APTT, PT, and TT (14 and 49 mg/kg/day), and decreases in circulating plasminogen levels (3 treatment groups) were noted. Dose-dependent increases in the titers of anti-rSTAR antibodies and neutralizing rSTAR activity were observed in the three treated groups. Increased neutralizing rSTAR activity diminished the pharmacologic effects of rSTAR (ie, prolonged APTT, PT, and TT approaching baseline levels at week 2). Histopathological findings included hemorrhage, and perivascular inflammatory cell infiltration at the injection sites, heptocellular degeneration characterized as cytoplasmic eosinophilia, vacuolation and condensed nuclei (49 mg/kg/day), effusion of RBCs and plasma within some Bowman's capsules and hyaline casts within the lumen of some renal tubules in the kidneys (14 and 49 mg/day/kg), and mild to moderate megakaryocyte hypoplasia with varying levels of pyknotic nuclei at all dose levels. Immune deposits in glomeruli in the kidneys from the three treated groups were detected. These changes were reversible following a 4-week recovery period. In the present preclinical evaluation of toxicity in monkeys, rSTAR is well tolerated at doses up to 49 mg/kg/day. The toxic target organs are the liver, kidney, and bone marrow.
Key Words: Recombinant staphylokinase • nonhuman primates • hepatoxicity • nephrotoxicity • antibody formation.
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Toxicologic Pathology, Vol. 31, No. 1,
14-21 (2003)
DOI: 10.1080/01926230390173815
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